A number of derivatives of acridine have recently been studied for antitumour activity. In earlier work with the 9-anilinoacridines the marked antitumour effect of the 1'-methanesulphonamide derivative 4'-(9-acridinylamino) methanesulphonanilide or AMSA was revealed (G. J. Atwell, B. F. Cain and R. N. Seelye, J.Med. Chem., 15, 611-615 (1972). A search for more dose-potent congeners culminated in the development of the clinical agent 4'-(9-acridinylamino) methanesulphon-m-aniside, m-AMSA or amsacrine. (See the following articles: B. F. Cain and G. J. Atwell, Europ. J. Cancer 10, 539-549 (1974); B. F. Cain, G. J. Atwell and W. A. Denny, J.Med.Chem., 18, 1110-1117 (1975); B. F. Cain, W. R. Wilson and B. C. Baguley, Molecular Pharmacology, 12, 1027-1035 (1976); B. F. Cain, G. J. Atwell and W. A. Denny, J.Med.Chem., 19, 772-777 (1976); B. F. Cain and G. J. Atwell, J.Med.Chem., 19, 1409-1416 (1976); M. J. Waring, Europ.J. Cancer, 12, 995-1001 (1976); B. C. Baguley, W. R. Wilson, L. R. Ferguson and B. F. Cain, Current Chemotherapy, pp.1210-1212 (1978); W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 21, 5-10 (1978).)
The antitumour activity of a large range of AMSA and m-AMSA analogues containing variously substituted acridine nuclei has now been investigated, see for example G. J. Atwell, B. F. Cain and R. N. Seelye, J.Med.Chem., 15 611-615 (1972); B. F. Cain, R. N. Seelye and G. J. Atwell, J.Med.Chem., 17, 922-930 (1974); B. F. Cain, G. J. Atwell and W. A. Denny, J.Med.Chem., 18, 1110-1117 (1975), and J.Med.Chem., 19, 772-777 (1976); B. F. Cain and G. J. Atwell, J.Med.Chem., 19, 1124-1129 and 1409-1416 (1976); G. J. Atwell, B. F. Cain and W. A. Denny, J.Med.Chem., 20, 520-526, 987-996, 1128-1134, and 1242-1246 (1977); W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 21, 5-10 (1978); W. A. Denny and B. F. Cain, J.Med.Chem., 21, 430-437 (1978); B. F. Cain, B. C. Baguley and W. A. Denny, J.Med.Chem., 21, 658-668 (1978); L. R. Ferguson and W. A. Denny, J.Med.Chem., 22, 251-255 (1979); W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 22, 1453-1460 (1979); L. R. Ferguson and W. A. Denny, J.Med.Chem., 23, 269-274 (1980); B. C. Baguley, W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 24, 520-525 (1981); L. R. Ferguson and B. C. Baguley, Mutation Research, 82, 31-39 (1981); W. A. Denny, B. F. Cain, G. J. Atwell, C. Hansch, A. Panthananickal and A. Leo, J.Med.Chem., 25, 276-315 (1982); B. F. Cain, G. J. Atwell, B. C. Baguley and W. A. Denny, U.S. Pat. application Ser. No. 386,104, filed June 7, 1982 as a continuation-in-part of U.S. Pat. application Ser. No. 187,517 filed Sept. 15, 1980; and B. F. Cain and G. J. Atwell, U.S. Pat. No. 4,366,318, issued Dec. 28, 1982. During this work a number of derivatives containing different oxygen-containing substituents were evaluated at the 1'-position (e.g. NHCOCH.sub.3, NHCOOCH.sub.3, COOH) but these compounds were less active and/or less dose potent than those bearing the methanesulphonamide (B. C. Baguley, W. A. Denny, G. J. Atwell and B. F. Cain, J.Med.Chem., 24, 170-177 (1981).
The preparation of various 7-amino and 7-(mono-and dialkylaminoalkylamino)-benzo [b][1,10] phenanthrolines and the evaluation of these compounds for antimalarial and antiamebic properties has been reported J. Dobson and W. O. Kermack, J.Chem.Soc. pp 150-155 (1946) and E. F. Elslager and F. H. Tendick, J.Med.Pharm.Chem., 5, pp 546-558 (1962).